The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, and opioids on physiology of this system. The NAc medium spiny GABAergic neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to the rewarding properties of these drugs. To investigate the actions of cannabinoids (CBs) in the NAc, we performed whole-cell recordings from MSNs in rat brain slices. Accomplishments attributable to this project in the past year include the establishment of a chronic delta-9-tetrahydrocannabinol (THC) treatment paradigm that successfully resulted in tolerance to various pharmacological effects of THC. This tolerance was also noted in the diminished inhibition of field excitatory postsynaptic potentials (EPSPs)in the nucleus accumbens shell. In addition to this significant alteration of cannabinoid receptors to exogenous cannabinoids, we have found in the past year that the process of long-term depression (LTD) of glutamatergic synaptic transmission was also blocked by chronic exposure to THC. This is important because it is though that LTD represents one of the mechanisms through which long-term changes in brain circuits occurs, and because the process of LTD, itself, depends upon endogenous cannabinoids produced in the brain. Therefore, we believe that our data support the hypothesis that chronic exposure to THC can reduce sensitivity of the brain to this drug, as well as sensitivity to endogenous cannabinoid molecules that seem to be involved in regulating the long-term strength of synaptic processes. This suggests that chronic THC use in humans may alter the ways in which normal neural processes occur in the brain. In addition, it is possible that this disruption in LTD by chronic THC may be associated with the development of addiction to this and other drugs. These data were published in the Journal of Neuroscience. In addition, we have begun to investigate the effects of repeated cocaine administration on synaptic inputs to MSNs. To do this, we have taken advantage of rats that express a fluorescent marker in a select population of MSNs following cocaine sensitization. By visualizing these specific neurons in our slice preparation, combined with intracellular recordings from these cells, we are able to address whether glutamatergic synaptic inputs to these specific neuronal populations are altered following repeated cocaine administration. These studies are ongoing, and preliminary data are to be presented at the 2004 Society for Neuroscience Annual Meeting.